JP3227497B2 - β-lactam compound and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel β-lactam compound and a method for producing the same.

[0002]

DISCLOSURE OF THE INVENTION The β-lactam compound of the present invention is a novel compound which has not been described in any literature, and is represented by the following general formula (1).

[0003]

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[Wherein R ¹ represents a hydrogen atom, a halogen atom, an amino group or a protected amino group. R ² is a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group,
A lower alkyl group, a lower alkyl group having a hydroxyl group or a protected hydroxyl group as a substituent, a hydroxyl group or a protected hydroxyl group; R ¹ and R ² may together represent the group ＯO. R ³ represents a hydrogen atom or a carboxylic acid protecting group. R ⁴ represents an aryl group which may have a substituent. R ⁵ represents a C _2-6 alkyl group, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent or a substituent. And a nitrogen-containing aromatic heterocyclic group which may be present. The β-lactam compound of the above general formula (1) is an important intermediate for synthesizing a penum, penem or cephem antibiotic as described below, for example.

[0005] Each group shown in the present specification is specifically as follows. In the following description, unless otherwise specified, a halogen atom means fluorine, chlorine, bromine,
It means iodine atom and the like. A lower alkyl group is, for example,
Means butyl, a straight-chain or branched C ₁ -C ₄ alkyl group such as a tert- butyl group - methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, sec.
The aryl group means, for example, a phenyl or naphthyl group.

The protected amino group represented by R ¹ includes, for example, phenoxyacetamide, p-methylphenoxyacetamide, p-methoxyphenoxyacetamide, p-chlorophenoxyacetamide, p-bromophenoxyacetamide, phenylacetamide, p-methyl Phenylacetamide, p-methoxyphenylacetamide, p-chlorophenylacetamide, p-bromophenylacetamide, phenylmonochloroacetamide, phenyldichloroacetamide, phenylhydroxyacetamide, phenylacetoxyacetamide,
α-oxophenylacetamide, thienylacetamide, benzamide, p-methylbenzamide, pt-
Butylbenzamide, p-methoxybenzamide, p-
Chlorobenzamide, p-bromobenzamide, or
Protective Groups in Organic Synthesis by Theodora W. Greene
Organic Synthesis ”(hereinafter simply referred to as“ Literature ”)
(P. 218-287) or phenylglycylamido and amino-protected phenylglycylamido, p-hydroxyphenylglycylamido and amino, hydroxyl or both are protected. P-hydroxyphenylglycylamide.
Examples of the protecting group for the amino group of phenylglycylamide and p-hydroxyphenylglycylamide include the groups described in Chapter 7 (pages 218 to 287) of the above document. Further, as the protecting group for the hydroxyl group of p-hydroxyphenylglycylamido, those described in Chapter 2 (10
To page 72).

The lower alkoxy group represented by R ² includes, for example, straight or branched chains such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. C _1-
A C ₄ alkoxy group can be exemplified.

The lower acyl group represented by R ² includes, for example, a linear or branched C ₁ -C ₄ acyl group such as formyl, acetyl, propionyl, butyryl and isobutyryl.

[0009] The protected hydroxyl group of a lower alkyl group having a hydroxyl group or a protected hydroxyl group as a substituent represented by R ² and the protected hydroxyl group of a protected hydroxyl group represented by R ² are described in Chapter 2 of the above document. (Pages 10 to 72). The above-mentioned substituted lower alkyl group represented by R ² may be the same or different type of a substituent selected from a hydroxyl group or the protected hydroxyl group shown above, and may be substituted on the same or different carbon by one or more. Good.

The protecting group for the carboxylic acid represented by R ³ includes benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, trichloroethyl,
tert-butyl group or Chapter 5 of the above document (chapter 152-1)
P. 92).

The types of the substituent which may be substituted on the aryl group represented by R ⁴ include a halogen atom, a hydroxyl group,
Represented by a nitro group, a cyano group, an aryl group, a lower alkyl group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a mercapto group, a group R ⁸ S- (R ⁸ is a lower alkyl group or an aryl group) alkylthio group or an arylthio group, a formyloxy group, a group R ⁸ COO-
An acyloxy group represented by (R ⁸ is as defined above), a formyl group, an acyl group represented by group R ⁸ CO- (R ⁸ is as defined above), a group R ⁸ O- (R ⁸ is defined as above) alkoxy group or aryloxy group represented, a carboxyl group, an alkoxycarbonyl group or the group R ⁸ OCO- (R ⁸ is as defined above) represented by the exemplified such an aryloxycarbonyl group. The aryl group for R ⁴ may be substituted with one or more substituents of the same or different types selected from the above substituents.

The alkenyl group of the alkenyl group which may have a substituent represented by R ⁵ includes, for example, vinyl,
1-propenyl, 2-propenyl, 1-butenyl, 2-
Butenyl, allyl, 1-cyclohexenyl group and the like. Examples of the alkynyl group of the optionally substituted alkynyl group represented by R ⁵ include ethynyl, 1-
And propynyl and 1-butynyl groups. Examples of the nitrogen-containing aromatic heterocyclic group of the nitrogen-containing aromatic heterocyclic group which may have a substituent represented by R ⁵ include, for example, thiazole-
2-yl, thiadiazol-2-yl, benzothiazol-2-yl, oxazol-2-yl, benzoxazol-2-yl, imidazol-2-yl, benzimidazol-2-yl, pyramidinyl, pyridyl group and the like. Can be Alkenyl groups represented by these R ^5, the alkynyl group, an aryl group or a nitrogen-containing aromatic heterocycle substituted and each may be a substituent group include the same substituent as substituent in R ^4. The alkenyl group, alkynyl group, aryl group or nitrogen-containing aromatic heterocyclic group for R ⁵ is one or more substituents of the same or different kind selected from the above substituents, and one or more substituents on the same or different carbons. It may be.

Examples of the substituent which may be substituted on the lower alkyl group or the aryl group represented by R ⁶ include the same substituents as those for R ⁴ . The lower alkyl group or the aryl group for R ⁶ is one or more substituents of the same or different types selected from the above substituents,
One or more carbon atoms may be substituted on the same or different carbons.

The compound of the present invention represented by the above general formula (1) is, for example,

[0015]

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Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above. R ⁶ represents a fluorine atom, a lower alkyl group which may have a substituent or an aryl group which may have a substituent. An azetidinone derivative represented by the general formula (R ⁷ ) ₃ —Sn—R ⁵ (3) wherein R ⁷ represents a lower alkyl group. R ⁵ is the same as above. And an organotin compound represented by the following formula:

In the present invention, the azetidinone derivative represented by the general formula (2) to be used as a starting material is produced, for example, according to the method described in JP-A-61-165368.

In preparing the compound of the general formula (1) of the present invention, the compound of the general formula (2) is prepared by adding the compound of the general formula (2) in an appropriate solvent in the presence of a palladium catalyst. And react with.

Specific examples of the organotin compound represented by the general formula (3) include, for example, tetraethyltin, tetrabutyltin, vinyltributyltin, (Z) -1-propenyltributyltin, 1- (tributylstannyl) -2
-Methylpro-1-pen, (trifluorovinyl) tributyltin, 1- (tributylstannyl) -1-propyne, (p-methoxyphenyl) tributyltin, 1-methyl-2- (tributylstannyl) pyrrole, (4- t
-Butyl-1-cyclohexen-1-yl) trimethyltin, (4-t-butyl-1-cyclohexen-1-yl) tributyltin, (E) -1,2-bis (tributylstannyl) ethylene, [p- (Trifluoromethyl) phenyl] tributyltin, vinyltributyltin, 1-
Examples thereof include methoxy-1- (tributylstannyl) ethylene, aryltributyltin, ethynyltributyltin, (phenylethynyl) tributyltin and the like. The amount of the organotin compound represented by the general formula (3) is usually about 1 to 3 times, preferably about 1 to 2 times the mol of the compound of the general formula (2).

Examples of the palladium catalyst include palladium acetate, palladium chloride, palladium bromide, palladium iodide, palladium nitrate, palladium sulfate, palladium acetoacetate, palladium oxide, bis (acetonitrile) palladium dichloride, and bis (phenylacetonitrile) dichloride. Divalent palladium salts such as palladium chloride and bis (triphenylphosphine) palladium chloride, tetrakis (triphenylphosphine) palladium, tetrakis (tri-2-furylphosphine) palladium, tetrakis (tri-2-thienylphosphine) palladium, tris Zero-valent palladium such as (dibenzylideneacetonyl) bispalladium, tris (dibenzylideneacetone) dipalladium and bis (dibenzylideneacetone) palladium can be exemplified. The amount of the palladium catalyst to be used is 0.1 to the azetidinone derivative of the general formula (2).
It is good to be about 01 to 1 times mol, preferably about 0.01 to 0.5 times mol.

As the solvent, conventionally known solvents can be widely used as long as they dissolve the compound of the formula (2) and are inert under the reaction conditions. Examples thereof include dichloromethane, chloroform, dichloroethane, trichloroethane and dibromoethane. , Propylene dichloride, carbon tetrachloride, halogenated hydrocarbons such as freon, tetrahydrofuran,
Cyclic ethers such as dioxane, acetonitriles, propionitrile, butyronitrile, isobutyronitrile, nitriles such as valeronitrile, amides such as dimethylacetamide, dimethylformamide, N-methylpyrrolidinone, and dimethylsulfoxide. And these may be used alone or as a mixture of two or more. The amount of these solvents used is determined by the amount of compound 1k
Usually about 0.5 to 200 l per g, preferably 1 to 50
It is better to be about l.

The above reaction is usually carried out at a temperature in the range of -60 to 100 ° C, preferably -50 to 50 ° C, and the reaction time is generally about 0.1 to 24 hours.

The azetidinone derivative of the general formula (1) thus obtained can be obtained as a substantially pure product by performing a usual extraction operation, crystallization operation and the like after completion of the reaction, but it can also be obtained by other methods. Of course, it can be purified.

General formula

[0025]

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Wherein R ¹ , R ² and R ³ are as defined above. 2-exomethylene cephem derivatives represented by] in a suitable organic solvent to Azechinon derivative represented by the general formula R ⁵ is a vinyl group (1), one general formula [In the formula, R ⁹ represents an aryl group which may have a substituent.
You . M represents a metal atom. Nucleophile represented by the general formula

[0027]

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Wherein R ¹ , R ² , R ³ and R ⁹ are as defined above. Give represented by 2-substituted-3-cephem compound], then manufacturing by the exerting a base to 2-substituted-3-cephem compounds obtained.
Where the aryl group represented by R ⁹ may be substituted
Examples of the group include the same substituents as the substituents for R ⁴
it can. The aryl group represented by R ⁹ is selected from the above substituents
Same or different types of substituents selected
One or more carbon atoms may be substituted.

The azetidinone derivative of the general formula (1) and the nucleophile of the general formula (5) are usually used in an amount of about 1 to 3 equivalents, preferably 1 to 1.5 equivalents of the former to the former.
It is better to use about equivalent. The reaction is performed in a suitable organic solvent. Here, as the organic solvent, general formula (1)
As long as it dissolves the azetidinone derivative represented by and is inert to the reaction, conventionally known ones can be widely used, for example, methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, Butyl acetate, methyl propionate, lower alkyl esters of lower carboxylic acids such as ethyl propionate, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether,
Dibutyl ether, methyl cellosolve, ethers such as dimethoxyethane, tetrahydrofuran, cyclic ethers such as dioxane, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, nitriles such as valeronitrile, benzene, toluene, xylene,
Substituted or unsubstituted aromatic hydrocarbons such as chlorobenzene and anisole, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, propylene dichloride, and carbon tetrachloride; and aliphatic hydrocarbons such as pentane, hexane, heptane, and octane , Cyclopentane,
Examples thereof include cycloalkanes such as cyclohexane, cycloheptane and cyclooctane; amides such as dimethylformamide and dimethylacetamide; and dimethylsulfoxide. In the present invention, these solvents can be used alone or in combination of two or more. These solvents also include
Water may be contained as needed. The amount of these solvents to be used is generally 0.1 per kg of the compound of the general formula (1).
It is good to use about 5 to 200 l, preferably about 1 to 50 l. The reaction is carried out at -70 to 180 ° C, preferably-
The reaction is carried out in the range of 50 to 120 ° C, and the reaction time is generally about 0.5 to 30 hours.

In the present invention, the 2-substituted methyl-3-cephem compound of the general formula (6) can be isolated by a usual extraction and purification method during the reaction, but the reaction with the base in the reaction solution can be performed. Can be continued. Here, as the base, for example, an aliphatic amine and an aromatic amine can be suitably used. As a specific example,
Triethylamine, diisopropylamine, ethyldiisopropylamine, tributylamine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8
-Diazabicyclo [5.4.0] undecene-7 (DB
U), 1,4-diazabicyclo [2.2.2] octane (DABCO), piperidine, N-methylpiperidine,
Examples thereof include 2,2,6,6-tetramethylpiperidine, morpholine, N-methylmorpholine, N, N-dimethylaniline, and N, N-dimethylaminopyridine.
These may be used alone or in combination of two or more. The amount of the base to be used is about 1 to 10 equivalents, preferably about 1 to 5 equivalents to the 2-substituted methyl-3-cephem compound represented by the general formula (6). The reaction is carried out at -70 to 180 ° C, preferably at -5.
The reaction is carried out at a temperature in the range of 0 to 120 ° C., and the reaction time is generally 0.1.
It is about 1 to 30 hours.

When it is not necessary to isolate the 2-substituted methyl-3-cephem compound of the general formula (6),
From the beginning of the reaction, a nucleophile of the general formula (5) and a base may simultaneously act on the azetinone derivative of the general formula (1). In this case, the amount of the nucleophile to be used is generally about 0.001 to 2.0 equivalents, preferably about 0.001 to 1.5 equivalents, to the compound of the general formula (1).

[0032]

According to the present invention, there is provided a novel β-lactam compound useful as a synthetic intermediate for cephem antibiotics.

[0033]

The present invention will be further clarified with reference to the following examples and reference examples.

Embodiment 1

[0035]

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R ¹ = phenylacetamide, R ² = H,
R ³ = p-methoxybenzyl, R ⁴ = phenyl, R ⁶ =
A trifluoromethyl compound of the general formula (2) (hereinafter, referred to as “compound (2a)”) (100 mg) and palladium acetate (6.1 mg) were weighed, dried under reduced pressure, and then replaced with nitrogen. Add N-methylpyrrolidinone (1 ml)
To make a homogeneous solution, vinyl tributyl tin (60
μl), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was transferred to a separating funnel using ethyl acetate, and washed with water and saturated saline. Then, after drying (Na ₂ SO ₄ ) and concentration, a crude product was obtained. This product was purified by column chromatography to obtain R ¹ = phenylacetamide, R ^1
2 = ^H, R 3 = p- methoxybenzyl, ^{R 4} = phenylene <br/> Le, compounds of ^{R 5} = formula vinyl (1) (hereinafter "Compound (1a)" hereinafter) (59.7 mg, Yield 72
%)was gotten.

NMR (CDCl ₃ ): δ ppm; 2.0
5 (s, 3H), 3.66 (ABq, 2H, J = 16.
7 Hz), 3.81 (s, 3H), 4.71 (dd, 1
H, J = 7.3 Hz, 5.4 Hz), 5.03 and 5.
16 (ABq, 2H, J = 11.9 Hz), 5.49
(D, 1H, J = 11.3 Hz), 5.64 (d, 1
H, J = 17.3 Hz), 5.81 (d, 1H, J =
5.4 Hz), 5.92 (d, 1H, J = 7.3H)
z), 7.52 (dd, 1H, J = 17.3 Hz, 1
(1.3 Hz), 6.90-7.74 (m, 14H).

Example 2 In Example 1, 2-vinyl was used instead of vinyltributyltin.
The reaction was carried out for 22 hours using propenyltributyltin, R ¹ = phenylacetamide, R ² = H, R ³ = p
-Methoxybenzyl, R ⁴ = phenyl and R ⁵ = 2-propenyl (hereinafter referred to as “compound (1
b) ") in a yield of 50%.

NMR (CDCl ₃ ): δ ppm; 1.7
8 (d, 3H, J = 1.5 Hz), 2.06 (s, 3
H), 3.60 and 3.64 (ABq, 2H, J = 1
7.7 Hz), 3.80 (s, 3H), 4.58 (d,
1H, J = 1.5 Hz), 4.76 (dd, 1H, J =
1.5 Hz, 1.5 Hz), 4.86 (dd, 1H, J
= 7.4 Hz, 5.2 Hz), 4.99 and 5.04
(ABq, 2H, J = 11.9 Hz), 5.83 (d,
1H, 5.2 Hz), 5.99 (d, 1H, J = 7.4)
Hz, NH), 6.87-7.76 (m, 14H).

Example 3 In Example 1, 2-vinyl was used in place of vinyltributyltin.
The reaction was carried out for 24 hours using methyl-1-propenyltributyltin, R ¹ = phenylacetamide, R ² =
H, R ³ = p-methoxybenzyl, R ⁴ = phenyl, R
⁵ = 2-methyl-1-propenyl compound of the general formula (1) (hereinafter referred to as “compound (1c)”) in a yield of 20%
Was obtained.

NMR (CDCl ₃ ): δ ppm; 1.5
7 (s, 3H), 1.74 (s, 3H), 2.06
(S, 3H), 3.58 and 3.65 (ABq, 2H,
J = 22.0 Hz), 3.81 (s, 3H), 4.81
(Dd, 1H, J = 7.2 Hz, 5.2 Hz), 4.9
7 and 5.10 (ABq, 2H, J = 11.9 Hz),
5.83 (d, 1H, 5.2 Hz), 5.91 (d, 1
H, J = 7.2 Hz), 6.09 (s, 1H), 6.9
8-7.73 (m, 14H).

Example 4 In Example 3, the reaction was carried out for 24 hours using tris (dibenzylideneacetone) dipalladium instead of palladium acetate as a palladium catalyst, whereby compound (1c) was obtained in a yield of 67%. The NMR spectrum of this compound completely matched that of the compound (1c) obtained in Example 3.

Embodiment 5

[0044]

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A compound of the general formula (2) in which R ¹ = R ² = H, R ³ = diphenylmethyl, R ⁴ = phenyl, and R ⁶ = trifluoromethyl (hereinafter referred to as “compound (2b)”) (391 mg) And palladium acetate (27.4m
To g), N-methylpyrrolidinone (4 ml) was added and stirred, and vinyltributyltin (268 μl) was added. After stirring at room temperature for 1 hour, the mixture was extracted with an ethyl acetate-potassium fluoride aqueous solution and washed with water. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the remaining solution was purified by column chromatography, where R ¹ = R ² = H, R ³ =
A compound of the general formula (1) in which diphenylmethyl, R ⁴ = phenyl and R ⁵ = vinyl (hereinafter referred to as “compound (1d)”) (250 mg, yield 79%) was obtained.

NMR (CDCl ₃ ): δ ppm; 1.9
2 (s, 3H), 3.01 (dd, 1H, J = 2.8H
z, 15.9 Hz), 3.52 (dd, 1H, J = 5.
6 Hz, 15.9 Hz), 5.49 (dd, 1H, J =
0.9Hz, 12.1Hz), 5.58 (dd, 1H,
J = 2.8 Hz, 5.6 Hz,), 5.64 (dd, 1
H, J = 0.9 Hz, 16.2 Hz), 6.93 (s,
1H), 7.25-7.63 (m, 16H).

Reference Example 1

[0048]

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Compound (1d) (30.4 mg) and sodium benzenesulfinate (12 mg) were weighed, and dimethylformamide (0.3 ml) was added thereto, followed by stirring.
After stirring for 1 hour, the reaction solution was extracted with ethyl acetate-water and washed twice with water. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the remaining liquid was used as it was in the next reaction.
Dimethylformamide (0.3 ml) was added to the residue, and the mixture was stirred and stirred at room temperature for diisopropylethylamine (40.8 μm).
l) was added. Stir at room temperature for 2 hours and add ethyl acetate
Extracted with water. Washing was carried out twice and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain a compound of the general formula (4) in which R ¹ = R ² = H and R ³ = diphenylmethyl (hereinafter referred to as “compound (4a)” (17) .8 mg, 81%).

NMR (CDCl ₃ ): δ ppm; 2.0
7 (s, 3H), 2.97 (dd, 1H, J = 2.2H)
z, 15.6 Hz), 3.59 (dd, 1H, J = 4.
8 Hz, 15.6 Hz), 4.80 (dd, 1H, J =
2.2Hz, 4.8Hz), 5.53 (s, 1H),
5.74 (s, 1H), 7.02 (s, 1H), 7.2
5-7.48 (m, 10H).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI B01J 31/12 C07B 61/00 300 C07B 61/00 300 C07D 205/08 R C07D 205/095 U (72) Inventor Takashi Shiroi Tokushima 51-41 Nishinosu, Taimahama, Kitajima-cho, Itano-gun, Japan (72) Inventor Yutaka Kameyama 24-194 Okuda-cho, Okayama-shi, Okayama Prefecture (56) References JP-A-51-110593 (JP, A) U.S. Pat. , A) Synlett, (1991), (12), p. 888-90 (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 205/09 C07D 205/095 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula [In the formula, R ¹ represents a hydrogen atom, a halogen atom, an amino group or a protected amino group. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group, a lower alkyl group, a lower alkyl group having a hydroxyl group or a protected hydroxyl group as a substituent, a hydroxyl group or a protected hydroxyl group. R ¹ and R ² may together represent the group ＯO. R ³ represents a hydrogen atom or a carboxylic acid protecting group.
R ⁴ represents an aryl group which may have a substituent. R
⁵ is an alkyl group of C _2-6, optionally substituted alkenyl group, which may have a substituent alkynyl group or
It represents an aryl group which may have a substituent. ] -Lactam compound represented by the formula: 2. A compound of the general formula Wherein R ¹ , R ² , R ³ and R ⁴ are the same as above. R ⁶ represents a fluorine atom, a lower alkyl group which may have a substituent or an aryl group which may have a substituent. In the presence of a palladium catalyst, the azetidinone derivative represented by
Formula (R ⁷ ) ₃ —Sn—R ^{5 wherein} R ⁷ represents a lower alkyl group. R ⁵ is the same as above. The method for producing a β-lactam compound according to claim 1, wherein the reaction is carried out with an organotin compound represented by the formula: